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Gross, E.* ; Meul, C.* ; Raab, S.* ; Propping, C.* ; Avril, S.* ; Aubele, M. ; Gkazepis, A.* ; Schuster, T.* ; Grebenchtchikov, N.* ; Schmitt, M.* ; Kiechle, M.* ; Meijer, J.* ; Vijzelaar, R.* ; Meindl, A.* ; van Kuilenburg, A.B.*

Somatic copy number changes in DPYD are associated with lower risk of recurrence in triple-negative breast cancers.

Br. J. Cancer 109, 2347-2355 (2013)
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Background:Genomic rearrangements at the fragile site FRA1E may disrupt the dihydropyrimidine dehydrogenase gene (DPYD) gene which is involved in 5-fluorouracil (5-FU) catabolism. In triple-negative breast cancer (TNBC), a subtype of breast cancer frequently deficient in DNA repair, we have investigated the susceptibility to acquire copy number variations (CNVs) in DPYD and evaluated their impact on standard adjuvant treatment.Methods:DPYD CNVs were analysed in 106 TNBC tumour specimens using multiplex ligation-dependent probe amplification (MLPA) analysis. Dihydropyrimidine dehydrogenase (DPD) expression was determined by immunohistochemistry in 146 tumour tissues.Results:In TNBC, we detected 43 (41%) tumour specimens with genomic deletions and/or duplications within DPYD which were associated with higher histological grade (P=0.006) and with rearrangements in the DNA repair gene BRCA1 (P=0.007). Immunohistochemical analysis revealed low, moderate and high DPD expression in 64%, 29% and 7% of all TNBCs, and in 40%, 53% and 7% of TNBCs with DPYD CNVs, respectively. Irrespective of DPD protein levels, the presence of CNVs was significantly related to longer time to progression in patients who had received 5-FU- and/or anthracycline-based polychemotherapy (hazard ratio=0.26 (95% CI: 0.07-0.91), log-rank P=0.023; adjusted for tumour stage: P=0.037).Conclusion:Genomic rearrangements in DPYD, rather than aberrant DPD protein levels, reflect a distinct tumour profile associated with prolonged time to progression upon first-line chemotherapy in TNBC.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Brca1 ; Copy Number Changes ; Dpyd ; Fragile Sites ; Triple-negative Breast Cancer; Dihydropyrimidine Dehydrogenase Gene ; Large Intragenic Rearrangements ; Dependent Probe Amplification ; Long-term Survival ; Fragile Sites ; Expression ; Cells ; 5-fluorouracil ; Chemotherapy ; Therapy
ISSN (print) / ISBN 0007-0920
e-ISSN 1532-1827
Zeitschrift British Journal of Cancer BJC
Quellenangaben Band: 109, Heft: 9, Seiten: 2347-2355 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Pathology (PATH)